To the Editor: Richardson et al. (June 16 issue)1 showed that,in relapsed multiple myeloma, bortezomib improved survival incomparison with high-dose dexamethasone. According to Trippoliet al.2 and Sonneveld et al.,3 life expectancy for patientswith myeloma who are alive at 1 year after treatment is about1.5 additional years (range, 0.253 to 2.472). Bortezomib costs49,077 ($59,991 in the United States at the current exchangerates) per patient on the basis of the schedule outlined inthe article and current Italian prices.4 Considering that sometreatment cycles are discontinued early because of side effectsor death, the incremental cost of bortezomib as compared withdexamethasone is about 40,000 ($48,942) per patient. Improvingsurvival by 14 percent at 1 year gives a lifetime gain of atleast 21 years (14 x 1.5) for every 100 patients. On the basisof these data, the cost per life-year gained for bortezomibas compared with dexamethasone is 190,476 ($232,924). This analysissuggests that the benefit of bortezomib has a cost that exceedscurrent international benchmarks.5
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-2498. [Free Full Text]
Trippoli S, Messori A, Becagli P, Alterini R, Tendi E. Treatments for newly diagnosed multiple myeloma: analysis of survival data and cost-effectiveness evaluation. Oncol Rep 1998;5:1475-1482. [ISI][Medline]
Sonneveld P, Suciu S, Weijermans P, et al. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol 2001;115:895-902. [CrossRef][ISI][Medline]
Decreto Ministeriale 26-1-2005. Gazzetta Ufficiale della Repubblica Italiana. February 4, 2005.
Messori A, Trippoli S, Vaiani M. Efficacy, safety, and cost of new anticancer drugs: price needs to be evaluated against effectiveness. BMJ 2002;325:1302-1302. [Medline]
To the Editor: In her editorial, Dispenzieri1 states that thesurvival analysis in the bortezomib trial reported by Richardsonet al. involved a 22 percent loss to follow-up. According tothe online Supplementary Appendix accompanying the full textof Richardson and colleagues' report, 150 patients were lostto follow-up. By back-calculation, we determined that the numberof deaths was about 135. Thus, the benefit of bortezomib couldeasily be wiped out if only 10 to 20 patients in the dexamethasonegroup died while lost to follow-up. In addition, there was aninsufficient length of follow-up and a severe censoring of thedisease-progression end point.1
Jan P. Vandenbroucke, M.D. Judith R. Kroep, M.D. Leiden University Medical Center 2300RC Leiden, the Netherlands j.p.vandenbroucke{at}lumc.nl
References
Dispenzieri A. Bortezomib for myeloma -- much ado about something. N Engl J Med 2005;352:2546-2548. [Free Full Text]
The authors reply: We greatly appreciate the questions fromDrs. Vandenbrouke and Kroep regarding some of the statisticalmethods. The reasons for censoring, including the number ofpatients lost to follow-up in the analyses of survival and thetime to progression, were inaccurate as provided in the SupplementaryAppendix, and we sincerely regret the error. A revised versionof the Supplementary Appendix is available with the full textof the article at www.nejm.org. In the survival analyses, thecorrect numbers of patients lost to follow-up were 11 (3 percent)and 6 (2 percent) in the bortezomib and dexamethasone groups,respectively. Therefore, only 2.5 percent of the patients werelost to follow-up in terms of survival, and it is highly unlikelythat the loss of 2.5 percent of the patients would significantlyaffect the results. Drs. Vandenbroucke and Kroep are correctin suggesting that the length of follow-up is limited, becauseonly 20 percent of the patients had died at the cutoff timefor data collection. However, this limitation was a result ofthe decision on the part of the independent data monitoringcommittee to recommend discontinuing treatment in the high-dosedexamethasone group and offer crossover to bortezomib afterthe prespecified interim analysis. It is possible that subsequentanalyses may be confounded by early crossover from high-dosedexamethasone to bortezomib, but the collection of survivaldata for both treatment groups is continuing, and we will presentthese updated results as soon as they are available.
We also appreciate the letter from Dr. Cecchi and colleaguesregarding the cost benefit of bortezomib. Their estimate ofthe cost-effectiveness of bortezomib in this letter is not correct.The mean number of treatment cycles in the study was 6 ratherthan 11. The mean body-surface area of patients was 1.89 m2rather than 2 m2. Furthermore, it is premature to use survivaldata to model cost-effectiveness on the basis of data from theAssessment of Proteasome Inhibition for Extending Remissions(APEX) trial, since fewer than one third of the events had occurredat the cutoff point for data collection. In a comprehensive,published analysis that was performed on the basis of data frompatients with relapsed and refractory myeloma and that accountedfor the costs of therapy, disease complications, and managementof adverse events, bortezomib, as compared with best supportivecare, had an incremental cost-effectiveness ratio of $45,356per life-year gained.1 In another analysis, bortezomib had anincremental cost-effectiveness ratio as low as 25,271 ($30,910)per life-year gained,2 suggesting that the ratio fell belowthe international benchmark.3,4 These findings suggest thatbortezomib is a cost-effective option for patients with relapsedmultiple myeloma.
Paul G. Richardson, M.D. Dana–Farber Cancer Institute Boston, MA 02115 paul_richardson{at}dfci.harvard.edu
Anthony L. Boral, M.D., Ph.D. Millennium Pharmaceuticals Cambridge, MA 02139
Kenneth C. Anderson, M.D. Dana–Farber Cancer Institute Boston, MA 02115
References
Mehta J, Duff SB, Gupta S. Cost effectiveness of bortezomib in the treatment of advanced multiple myeloma. Manag Care Interface 2004;17:52-61. [Medline]
Bagust A, Haycox AR, Boland A, et al. Economic evaluation of bortezomib (VELCADE) for relapsed and refractory multiple myeloma. Blood 2004;104:80a-80a. abstract.
Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. CMAJ 1992;146:473-481. [Abstract]
Messori A, Trippoli S, Vaiani M. Efficacy, safety, and cost of new anticancer drugs: price needs to be evaluated against effectiveness. BMJ 2002;325:1302-1302. [Medline]
Utecht, K. N., Kolesar, J.
(2008). Bortezomib: A novel chemotherapeutic agent for hematologic malignancies. Am J Health Syst Pharm
65: 1221-1231
[Abstract][Full Text]
49,077 ($59,991 in the United States at the current exchange rates) per patient on the basis of the schedule outlined in the article and current Italian prices.4 Considering that some treatment cycles are discontinued early because of side effects or death, the incremental cost of bortezomib as compared with dexamethasone is about 
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